UV/Vis-based process analytical technology to improve monoclonal antibody and host cell protein separation

Process analytical technology(PAT) is gaining more interest in the biomanufacturing industry because of its potential to improve operational control and compliance through real-time quality assurance.Currently, biopharmaceutical producers mainly monitor chromatographic processes with ultraviolet/visible(UV/Vis) absorbance. However, this measurement has a very limited correlation with purity and quantity. The current study aims to determine the concentration of monoclonal antibody(mAb) and host cell proteins(HCPs) using a build-in UV/Vis monitoring during Protein A affinity chromatography and to optimize the separation conditions for high purity of mAb and minimizing the HCPs content. The eluate was analyzed through in-line UV/Vis at 280 and 410 nm, representing mAb and HCPs concentration,respectively. Each 0.1 column volume(CV) fraction of UV/Vis chromatogram peak area were calculated,and different separation conditions were then compared. The optimum conditions of mAb separation were found as 12 CV loading, elution at pH 3.5, and starting the collection at 0.5 CV point, resulting in high m Ab recovery of 95.92% and additional removal of 49.98% of HCP comparing with whole elution pool. This study concluded that UV/Vis-based in-line monitoring at 280 and 410 nm showed a high potential to optimize and real-time control Protein A affinity chromatography for mAb purification from HCPs.

Raman spectroscopy as process analytical tool in downstream processing of biotechnology

Downstream processing or product recovery plays a vital role in the development of bioprocesses.To improve the bioprocess efficiency,some unconventional methods are much required.The continuous manufacturing in downstream processing makes the Process Analytical Technologies(PATs)as an important tool.Monitoring and controlling bioprocess are an essential factor for the principles of PAT and quality by design.Spectroscopic methods can apply to monitor multiple analytes in real-time with less sample processing with significant advancements.Raman spectroscopy is an extensively used technique as an analytical and research tool owing to its modest process form,non-destructive,non-invasive optical molecular spectroscopic imaging with computer-based analysis.Generally,its application is essential for the analysis and characterization of biological samples,and it is easy to operate with minimal sample.The innovation on various types of enhanced Raman spectroscopy was designed to enhance the Raman analytical technique.Raman spectroscopy could couple with chemometrics to provide reliable alternative analysis method of downstream process analysis.Thus,this review aims to provide useful insight on the application of Raman spectroscopy for PAT in downstream processing of biotechnology and Raman data analysis in biological fields.

A new PAT application: Optimization of processing methods for honeysuckle flower (Lonicerae Japonicae Flos) and wild honeysuckle flower (Lonicerae Flos)

Objective:A novel processing analytical framework of Chinese Material Medica (CMM) includes breeding process analysis,planting process analysis,producing process analysis and manufacture process analysis.In order to study this framework,we used quality control of honeysuckle flower (Lonicerae japonicae Flos) including diploid and tetraploid Lonicera japonica,and wild honeysuckle flower (Lonicerae Flos) including Lonicerae hypoglauca,Lonicerae confusa,Lonicerae fulvotomentosa and Lonicerae macranthoides as an example.Methods:A total of 360 samples were analyzed from three variables including species,growing areas,and optimization of processing methods.For quantitative analysis,chlorogenic acid (CA),isochlorogenic acid A (3,5-DCA),and isochlorogenic acid C (4,5-DCA) were measured with high performance liquid chromatography (HPLC).Results:The three organic acids contents are higher in wild honeysuckle flower than honeysuckle flower;L.japonica (tetraploid) is higher than L.japonica (diploid).Modern processing methods (kill-enzyme torrefaction and fixing machine drying) are popular in growing areas and are superior to traditional methods (sun and shade drying).Conclusions:Novel process analysis concepts in processing analytical technology (PAT) enriched the Chinese MateHal Medica contents.

Study progression in application of process analytical technologies on film coating

Film coating is an important unit operation to produce solid dosage forms,thereby,the monitoring of this process is helpful to find problems in time and improve the quality of coated products.Traditional methods adopted to monitor this process include measurement of coating weight gain,performance of disintegration and dissolution test,etc.However,not only do these methods cause destruction to the samples,but also consume time and energy.There have recently emerged the applications of process analytical technologies(PAT)on film coating,especially some novel spectroscopic and imaging technologies,which have the potential to real-time track the progress in film coating and optimize production efficiency.This article gives an overview on the application of such technologies for film coating,with the goal to provide a reference for the further researches.

Online pharmaceutical process analysis of Chinese medicine using a miniature mass spectrometer: Extraction of active ingredients as an example

The automation of traditional Chinese medicine(TCM)pharmaceuticals has driven the development of process analysis from offline to online.Most of common online process analytical technologies are based on spectroscopy,making the identification and quantification of specific ingredients still a challenge.Herein,we developed a quality control(QC)system for monitoring TCM pharmaceuticals based on paper spray ionization miniature mass spectrometry(mini-MS).It enabled real-time online qualitative and quantitative detection of target ingredients in herbal extracts using mini-MS without chromatographic separation for the first time.Dynamic changes of alkaloids in Aconiti Lateralis Radix Praeparata(Fuzi)during decoction were used as examples,and the scientific principle of Fuzi compatibility was also investigated.Finally,the system was verified to work stably at the hourly level for pilot-scale extraction.This mini-MS based online analytical system is expected to be further developed for QC applications in a wider range of pharmaceutical processes.

Using the Analytical Hierarchy Process Model in the Prioritization of Information Assurance Defense In-Depth Measures?—A Quantitative Study

Organizational computing devices are increasingly becoming targets of cyber-attacks, and organizations have become dependent on the safety and security of their computer networks and their organizational computing devices. Business and government often use defense in-depth information assurance measures such as firewalls, intrusion detection systems, and password procedures across their enterprises to plan strategically and manage IT security risks. This quantitative study explores whether the analytical hierarchy process (AHP) model can be effectively applied to the prioritization of information assurance defense in-depth measures. In response to these threats, the President, legislators, experts, and others have characterized cyber security as a pressing national security issue. The methods used in this study consisted of emailing study participants a survey requesting that they prioritize five defense in-depth information assurance measures, anti-virus, intrusion detection, password, smart-cards, and encryption, with a range of responses from 1 - 5 using a Likert scale to consider standard cost, effectiveness, and perceived ease of use in terms of protection of organizational computing devices. The measures were then weighted, based on ranking. A pair-wise comparison of each of the five measures is then made using AHP to determine whether the Likert scale and the AHP model could be effectively applied to the prioritization of information assurance measures to protect organizational computing devices. The findings of the research reject the H0 null hypothesis that AHP does not affect the relationship between the information technology analysts’ prioritization of five defense in-depth dependent variables and the independent variables of cost, ease of use, and effectiveness in protecting organizational devices against cyber-attacks.

Transformation and risk assessment of the East Kolkata Wetlands (India)using fuzzy MCDM method and geospatial technology

The East Kolkata Wetlands (EKW) is located on the eastern periphery of the city of Kolkata and extends up to theBidyadhari-Matla River confluence. It is a Ramsar Site and acts as an absorber basin for a large number of con-taminants drained from Kolkata. Agricultural lands, sewage-fed fisheries, garbage dumping fields, horticulture,and built-up areas are included in this protected area, that covers approximately 125 km2. It reveals that climatechange reduces the variety of wetland ecosystem services and increases socio-economic vulnerability and eco-nomic stress. The human encroachment, reclamation of land for agriculture, aquaculture, and urban expansion inand around Kolkata has recently adversely threatened the EKW. The remotely sensed data, socio-economic data,and responses of inhabitants have been used to analyse the EKW’s risk and vulnerability. We employed geospatialanalysis by using the Multi-Criteria Decision Making (MCDM) method using nine risk factors. An in-depth analysisof the EKW using geospatial techniques and the Fuzzy Analytic Hierarchy Process (FAHP) helped to understandthe EKW transformations through vulnerability and risk analysis. The results show that the transformation of thewetland to aquaculture, eutrophication and pollution, road proximity, waste dumping, population density, andgrowth are the main factors for the deteriorating health, quality, and environment of the EKW. It also reveals thatquantitative and qualitative evaluations of ecosystem services, wetland degradation, transformation, and cause-effect rapport should be periodically assessed using scientific methods like FAHP, RS, GIS to formulate resilient,integrated plans and strategy for the sustainable management of the EKW.

Process Characterization of the Transesterification of Rapeseed Oil to Biodiesel Using Design of Experiments and Infrared Spectroscopy

For optimization of production processes and product quality,often knowledge of the factors influencing the process outcome is compulsory.Thus,process analytical technology(PAT)that allows deeper insight into the process and results in a mathematical description of the process behavior as a simple function based on the most important process factors can help to achieve higher production efficiency and quality.The present study aims at characterizing a well-known industrial process,the transesterification reaction of rapeseed oil with methanol to produce fatty acid methyl esters(FAME)for usage as biodiesel in a continuous micro reactor set-up.To this end,a design of experiment approach is applied,where the effects of two process factors,the molar ratio and the total flow rate of the reactants,are investigated.The optimized process target response is the FAME mass fraction in the purified nonpolar phase of the product as a measure of reaction yield.The quantification is performed using attenuated total reflection infrared spectroscopy in combination with partial least squares regression.The data retrieved during the conduction of the DoE experimental plan were used for statistical analysis.A non-linear model indicating a synergistic interaction between the studied factors describes the reactor behavior with a high coefficient of determination(R^(2))of 0.9608.Thus,we applied a PAT approach to generate further insight into this established industrial process.

基于改进层次分析法的航天器量化风险分析方法

航天器研制风险的量化分析与评估能够有效提高资源投入和风险控制措施的精准性。为满足当前航天器项目对风险量化管理的要求,航天器风险识别与控制应覆盖研制全流程。文章采用改进层次(AHP)-模糊综合评价法,给出了风险分析与评估的方法及流程,并以遥感领域发射卫星为例,基于项目特点建立了覆盖技术、费用、质量、管理四个方面的风险要素集,运用专家打分得到风险评价隶属度矩阵,对风险等级进行科学量化,对项目间、项目内部风险要素进行分析,给出风险控制重点项目。在风险因素增多、项目数量上升的情况下,风险量化分析方法能够在比较项目间风险的严重程度、合理分配资源方面,为管理者提供更好的决策支撑。

以功效物质为质量目标的中药生产过程质量控制研究与实践

中药生产过程质量控制是影响中药产品质量的关键,但中药成分的多样性和生产过程的复杂性给过程质量的精准控制带来巨大挑战。首先提出了以功效物质为核心的中药智能化控制理念,系统阐释了中药质量的科学内涵,为中药复杂成分体系“控什么”“怎么控”提供了理论依据。同时,通过先进信息化、数字化和智能化技术,对中药生产过程开展了智改数转的研究和建设实践。最终建立了以功效物质为质量目标的中药生产过程质量控制体系,为解决过程质量控制难题提供了契机。

中国科学仪器上市企业科技创新能力综合评价

从创新投入、创新环境、创新产出、创新影响4个方面构建科学仪器企业科技创新能力评价指标体系,采用层次分析法、熵权法组合赋权,通过TOPSIS-障碍度模型对科学仪器企业的科技创新能力进行综合评价分析,以42家中国科学仪器上市企业为样本进行实证研究。研究发现目前制约我国科学仪器科技创新能力发展的最主要因素是产学研合作、产品与技术国际专利布局、研发投入等方面存在的问题。鉴于此,应加强以企业为主体的产学研用合作协同创新模式,持续加大研发投入力度,重视技术、软件的开发及知识产权保护等,优化国际市场布局,为科学仪器企业科技创新发展赋能。

装配式项目BIM技术应用风险管理研究

针对装配式项目在应用BIM技术时可能存在的风险与不确定性,将层次分析法与模糊综合评价相结合,建立基于模糊层次分析法的装配式项目应用BIM技术风险评价模型。首先,建立风险评价指标体系;其次,应用层次分析法确定风险评价指标权重、模糊综合评价建立风险评价模型;最后,经实证研究,应用该风险评价模型对装配式项目应用BIM技术进行风险因素分析及风险等级评定,为装配式项目应用BIM技术进行风险管理研究提供了方法借鉴。

Process analytical technologies and self-optimization algorithms in automated pharmaceutical continuous manufacturing

The pharmaceutical industry is now paying increased attention to continuous manufacturing.While the revolution to continuous and automated manufacturing is deepening in most of the top pharma companies in the world,the advancement of automated pharmaceutical continuous manufacturing in China is relatively slow due to some key challenges including the lack of knowledge on the related technologies and shortage of qualified personnels.In this review,emphasis is given to two of the crucial technologies in automated pharmaceutical continuous manufacturing,i.e.,process analytical technology(PAT)and self-optimizing algorithm.Research work published in recent 5 years employing advanced PAT tools and self-optimization algorithms is introduced,which represents the great progress that has been made in automated pharmaceutical continuous manufacturing.

苦参-黄柏药对的提取工艺研究

目的研究苦参-黄柏药对的提取工艺,为治疗肛肠疾病的新药开发提供参考依据。方法以苦参总碱(苦参碱+氧化苦参碱)含量、盐酸小檗碱含量、总黄酮含量及浸膏得率为评价指标,采用层次分析法-熵权法计算各指标权重系数,结合Box-Behnken设计-响应面法研究苦参-黄柏药对的最佳提取工艺并进行验证。结果苦参-黄柏药对的最优提取工艺为以12倍量58%乙醇浸泡30 min后提取2次,每次120 min。验证实验结果与预测值的相对误差为1.88%。结论所得提取工艺稳定、可行,可为苦参-黄柏药对的进一步应用与新药开发提供参考。

川楝子醋制工艺优化

目的优化川楝子醋制工艺。方法在单因素试验基础上,以加醋量、闷润时间、炒制时间为影响因素,川楝素、芦丁、异槲皮苷、水溶性浸出物含量的总评“归一值”(OD值)为评价指标,Box-Behnken响应面法结合层次分析(AHP)-熵权法优化醋制工艺。结果最佳条件为每100 kg饮片用38 kg醋,闷润115 min,文火炒制10 min(饮片表面温度70~90℃),OD值为90.67。结论该方法合理可行,可为醋川楝子工业化生产提供参考。

多指标综合评分结合层次分析法优化桑黄蜜炙工艺

目的 优化桑黄蜜炙工艺。方法 采用正交实验设计结合层次分析法,以内在质量(麦角甾醇、原儿茶醛、原儿茶酸含量)和外观性状评分为评价指标,对影响桑黄蜜炙工艺中的关键因素(蜜水比、蜜水与桑黄质量比、炒制温度、炒制时间)进行考察,确定桑黄蜜炙最佳工艺参数。结果 桑黄蜜炙最佳工艺为取桑黄生品(1 cm3方块状),加适量辅料拌匀(每100 kg的桑黄用炼蜜与水各25 kg),闷润2 h至辅料被吸尽,置于炒制容器内,在炒制温度130~140℃下炒制5 min,取出,置于50℃烘箱内2 h,取出,晾凉。3次验证实验结果的RSD为0.68%。结论 优选出的桑黄蜜炙工艺稳定、可行。

基于Box-Behnken响应面法与BP神经网络优化雪莲药渣化学成分提取工艺

目的 优化雪莲药渣提取工艺。方法 在测得提取液中绿原酸、芦丁和多糖含量的基础上采用层次分析法(AHP)赋权得到综合评分。以料液比、提取时间和提取次数为考察因素,以综合评分为优选指标,运用Box-Behnken响应面设计和BP神经网络优化雪莲药渣化学成分的提取工艺。结果 Box-Behnken响应面法优化的提取工艺为加9倍量水回流提取3次,每次提取42 min。选择响应面试验中的17组数据作为训练数据和验证数据,BP神经网络预测的优选的提取工艺为加6倍量水回流提取3次,每次煎煮30 min。验证试验结果表明,BP神经网络优化工艺实际综合评分高于响应面法实际综合评分,提示BP神经网络预测的优选的提取工艺更为合理。结论 BP神经网络预测的优选的提取工艺合理、稳定、可行,可为雪莲药渣的二次开发利用提供参考。

近红外光谱(NIR)和过程分析技术(PAT)

本文介绍了近些年兴起的过程分析技术(PAT)、在线近红外光谱技术的组成和实施以及国内外近红外光谱仪器的进展情况,提出了我国应重视过程分析技术的研究和应用以及近红外光谱仪的发展方向。

基于SET-AHP-TRIZ的坐式康复训练器设计研究

为解决现有坐式康复训练器形式与功能单一、操作使用缺乏智能化等问题,文章构建了基于SET-AHP-TRIZ的设计思路。首先,对产品的现状、用户进行市场调研,采用SET分析法确定目标产品的机会缺口;其次,应用AHP法对需求点进行定量计算,以确定创新过程中需要着重改善的问题;最后,通过应用TRIZ理论分析出现的矛盾问题,并总结其矛盾类型,利用发明原理解决问题,进行坐式康复训练器设计实践,减少了设计过程主观因素的影响,使设计结果更为科学合理,以期提高用户的满意度。

基于AHP的技术创新生态链演进影响因素研究

本文探究影响技术创新生态链发展的关键因素,对于推动技术创新、技术创新生态链乃至技术创新生态系统的演进发展具有重要作用。本文在分析技术创新生态链演进影响因素的基础上,采用层次分析法,构建技术创新生态链演进评价模型,构造判断矩阵,计算各指标所占权重并进行一致性检验。结果发现,资源流转状况、节点创新能力、节点关系和组织管理水平是影响技术创新生态链演进的关键因素,可以通过提升以上四个方面的状况来促进技术创新生态链的演进。